Natural antibodies (NA) occur in normal healthy individuals and are believed to form the front line of defense against foreign pathogens, like bacteria, fungi and viruses. The goal of this proposal is to characterize natural antibodies that are correlated with the incidence or avoidance of Alzheimer?s disease and the pathological significance of the immune response to amyloid. The overarching hypothesis is that the immune response to amyloid is similar to the immune response to microbial pathogens, where NA are produced by a T cell independent (TI) immune response and forms first response to the formation of amyloids. We hypothesize that NA and autoantibodies (AA) are associated with protection against AD and may serve as biomarkers of AD. We have developed a novel and unbiased method to characterize the spectrum of NA and AA in humans in terms of their preferred epitopes and mimotopes that these antibodies recognize by immunoselection of random sequences from a phage display library and determining the immunoreactive peptide sequences by MiSeq deep sequencing. Preliminary data shows that monoclonal antibodies against amyloids display distinct and specific sequence pattern preferences that can be used as a fingerprint to identify the antibody in complex mixtures of antibodies, like serum and that some antibodies in control individuals lacking disease have antibodies that are strongly correlated with avoiding disease. To confirm and validate these antigens, we will select epitope and mimotope sequences that are correlated with aging and AD and use them to construct a microarray of the top random sequences associated with aging and AD and we will determine how the levels of the specific antibodies correlate with aging and disease progression. These results hold the potential for identifying potentially therapeutic antibodies that are associated with protection against AD and antibodies that may serve as useful biomarkers of disease subtype, onset and progression. We will test whether anti-amyloid antibodies are produced by T-cell independent (TI) pathways involving the engagement of antigen with toll receptors. We will also determine whether the TI response is type 1 or type 2. Because TI antigens do not activate T cells and have a better safety profile, the results of this aim have important implications for the development of safe and effective active vaccination therapy that targets pathogenic amyloid aggregates without activating cytotoxic T cells that are associated with inflammatory side effects.